Foster, A.; (2005) A study of the action of inflammatory mediators on intracellular calcium in cultured rat sensory neurones. Doctoral thesis , University of London.

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Abstract

Tissue damage releases many endogenous mediators including ATP, serotonin (5-HT), histamine and prostaglandins such as PGE2. Many of these substances directly excite primary nerve endings to elicit either pain (ATP) or both pain and itch (histamine and 5-HT). Prostaglandins do not directly activate the nerve endings but are known to sensitise them to histamine and 5-HT. Although histamine is known to act on sensory neurones via the Hi histamine receptor, the receptor subtypes activated by ATP and 5-HT remain unclear. In addition, the mechanism by which prostaglandins sensitise the nerve endings is unknown. These issues have been investigated in cultured rat dorsal root ganglion neurones by using the ratiometric indicator Fura-2 to monitor changes in intracellular calcium. 5-HT evoked a rise in Ca2+ j in approximately a fifth of neurones. This proportion remained unchanged when cells were stimulated in a nominally calcium free solution or with the 5-HT2 receptor agonist, a-methyl 5-HT. Thus, sensory neurones responded to 5-HT via 5-HT2 receptors. PGE2 sensitised neurones to 5-HT as shown by a leftward shift in the dose response curves. A similar leftward shift was seen for the effect of PGE2 on the response to histamine. The effects of PGE2 could be mimicked by application of forskolin and were blocked by the protein kinase A (PKA) inhibitor, H89. This suggests that the sensitisation results from a phosphorylation reaction mediated by PKA. Three quarters of DRG neurones responded to ATP and a similar proportion responded to the P2Y agonist, 2-methyl thio ATP. However, although the response to the P2Y agonist was reduced by pretreatment with the PLC inhibitor U73122 it was not totally abolished, supporting the notion that P2X receptors were also involved. In conclusion, it appears that the calcium responses elicited by histamine and 5-HT in rat sensory neurons are primarily due to activation of G protein coupled receptors and that the sensitivity of these receptors was enhanced by PKA mediated phosphorylation.

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